Ketones (Background)
It is well understood that dietary restriction in the form of calorie deprivation and/or a low carbohydrate/high fat diet (LCHFD) is conducive to ketogenesis. Although hyperketonemia (>0.5 mmol/L of serum ketones), when induced by such dietary programs, has been shown to produce positive effects on biological markers of insulin resistance, serum glucose stabilization, diabetes, obesity, epilepsy, cognitive deficits, inflammation and even cancer, achievement and sustenance of functional serum ketone levels is a very difficult task. Achieving a state of ketosis requires dedication and sacrifice, while enduring states of malaise during energy substrate transition. For some, the achievement of ketosis is more difficult than for others based on metabolic, genetic, environmental, and lifestyle factors combined.
Sustained ketosis is also a state desired by athletes in pursuit of improved performance, as a function of ketones serving as substrates for mitochondrial ATP generation. Research shows that ketones produce as much as 38% more ATP per unit carbon than glucose as substrates of the TCA cycle. In addition, research shows ATP generation from ketones as substrates in the mitochondria instead of glucose results in fewer free radical by-products. Furthermore, ketones are shown to induce transcription and subsequent synthesis of endogenous antioxidants, thereby priming the generation of intracellular glutathione and other endogenous antioxidants to produce a proactive protection against oxidative stress.
Athletes in ketosis and under physical load are shown to operate at full power output with a lower VO2 max than those utilizing glucose (carbohydrate) as a primary source of ATP. When at elevated serum levels indicative of ketosis, ketones are also known to spare muscle (anticatabolic) when under stress, including stress caused by nutrient deprivation. Although ketosis is a metabolic state that does not fit optimally for everyone who attempts to achieve it, there are pharmacological benefits of ketones, such as beta-hydroxyl-butyrate/beta-hydroxybutyrate (BHB) and acetoacetate when they exist in hyperketonemic states. Healthy ketosis is represented by a state where ketones measure in the range 0.4-5.0 mmol/L, while blood sugar remains stable and at around baseline of 4.2-5.0 mmol/L.
Although it is known that ketones serve as substrates for efficient ATP generation, the means by which such ketones also serve as ligands for various receptors, such as hydroxyl carboxylic acid receptors (HCA), are not well understood. BHB is a known HCA2 receptor agonist and, therefore, it is expected to have some neuroprotective activity, vis-à-vis its activity on monocytes and macrophages.
During carbohydrate deprivation, serum glucose declines and the metabolism can shift to fatty acid beta-oxidation and the production of ketones. This is the essence of endogenous ketone induction. Although fatty acids cannot readily cross the blood brain barrier to serve neurons as an energy substrate amid carbohydrate deprivation, ketones are hydrophilic and can cross to serve efficiently as substrates for neuron ATP generation. Ketones can supply in excess of 50% of the brain's energy requirements during periods of glucose scarcity. The scarcity of glucose amid the abundantly available ketone causes cells to increase mitochondrial numbers, induce endogenous antioxidant generation, and activate various other protective mechanisms.
It has further been established that many neurological disorders are associated with impaired mitochondrial activity, compromised mitochondrial numbers, limited endogenous antioxidant status, elevated free radical generation, and oxidation amongst other pathological features and hallmarks. Ketosis has been shown to improve many of these pathological features.
In view of the foregoing, the exogenous supply of ketones may offer a number of pharmacological benefits, including both mental and physical benefits. A daily supply of exogenous ketones would alleviate the stress associated with diet adherence, and would allow for the pharmacological benefits of ketones to continue due to the maintenance of elevated serum ketone levels (despite the temporary or prolonged increment of serum glucose and stored glycogen that may ensue as a function of a meal or few days off a ketogenic cycle). An exogenous supplement of ketones would also provide an immediate and efficient transition back to a ketogenic lifestyle, without the associated energy deficit that is typically associated with the cell-switch-back to serum ketones and fat as an energy (ATP) substrate. Metabolic support during energy substrate scarcity would be another substantial benefit of an exogenous ketone supply, particularly in the context of calorie or carbohydrate deprivation for weight management or therapy of other types. An exogenously supply of ketones would further serve as a bridging energy source during a low-carbohydrate diet and fluctuations in dietary habits, whether those shifts are long-term initiatives or short-term breaks. An exogenous supply of ketones would serve to avert the state of malaise that is often attendant to a calorie/carbohydrate deprived state, and would improve appetite control and support cognitive alertness.
Butyrate (Background)
Short chain fatty acids, also known as volatile fatty acids, are those typically produced by the microbial community of the intestine. These microbes are often referred to as probiotics or microbiota. Such microbes comprise a significant component of the immune system. These symbiotic microbes produce short chain fatty acids from dietary fiber, i.e., fatty acids that serve as signaling ligands for various receptors involved in inflammatory control, including the HCA2 receptor (the above described beta-hydroxybutyrate (ketone) serves as an agonist for such receptor as well).
The short chain fatty acids of the intestinal lumen include most abundantly, butyrate, propionate, and acetate. Research shows that butyrate fed mice remain lean (despite dietary calorie load); avoid metabolic problems; have increased energy expenditure in the form of body heat generation; and tend to have higher physical activity. Butyrate has been shown to lower serum cholesterol in various studies and by as much as 25% in some studies, and reduce serum triglycerides by as much as 50% compared to controls. Butyrate has further been shown to lower fasting insulin by nearly 50%, and increase insulin sensitivity by as much as 300%. Still further, butyrate administration has been shown to improve appetite and food portion control.
Research has further shown that butyrate is a key fuel for epithelial cells of the intestinal tract and that it may improve gut lining integrity. Similar to BHB, butyrate is an inhibitor of HDAC to induce global changes in genetic transcription of genes encoding oxidative stress resistance. This down regulation of gene transcription results in improved protection from free radical damage associated with strained or extreme metabolic conditions (and environmental toxins). This genetic optimization provided by butyrate also includes neuroprotection, similar to that exhibited by BHB.
Still further, lumen butyrate has been shown to directly preserve gut friendly bacteria in the microbiota, while adversely affecting pathogenic bacteria like Escherichia coli, Salmonella spp. and Campylobacter spp. Passive absorption of water in the colon depends on short chain fatty acid availability. Butyrate has been shown to play a role in healthy peristalsis to help normalize movement in cases of constipation or diarrhea. Butyrate serves to support optimal hydration and optimal bowel elimination function. Butyrate has also been shown to exhibit trophic effects on intestinal cell proliferation, improving villi, and general lining health. In addition, butyrate has been shown to be a potent promoter of intestinal regulatory T cells establishing yet another immune regulating mechanism that promotes better inflammatory control at the mucosal lining. Promotion of gastrointestinal health provides a formidable platform for improved general and systemic health.
To compound the benefits offered by ketosis (as described above), it is known from the literature that butyrate induces FGF21 in serum, liver and adipocytes, which in turn stimulates fatty acid oxidation and hepatic ketone production. This serves as an inducing signal for ketosis, along with butyrate itself, thereby serving as a direct substrate for ketone production and energy generation. In short, butyrate serves as a significant synergistic force for ketosis induction; BHB ligand interactions and pharmacology; and general health, fitness and performance support.
As discussed above, an exogenous supply of ketones, such as BHB, will provide an immediate alternative energy (ATP) source during periods of calorie or carbohydrate deprivation. However, concurrent butyrate supplementation in the form of sodium, calcium or potassium butyrate (or its esters) will prompt the body to induce endogenous ketone synthesis; will serve as a ligand to stimulate receptors that the ketone will act on; will contribute to the improvement of insulin and general metabolic health; will support inflammatory and general immune system health; will improve gastrointestinal health and integrity—all in parallel with the benefits that concurrent supplementation of the sister ketone molecule will provide.
As the following will demonstrate, the compositions and methods of the present invention will be very useful for providing an exogenous supply of ketones, to provide a person with the numerous pharmacologic benefits described herein.